This proposal describes a five-year training program designed to facilitate transition to an academic physician- scientist career in Pulmonary and Critical Care Medicine. The principal investigator will complete Pulmonary and Critical Care fellowship training in December 2009 after which she will be appointed to the title of Instructor in the Department of Medicine. She will pursue her scientific research at the Wistar Institute under the mentorship of Dr. Ellen Puri. The proposed project is in the field of interstitial lung disease, with the goal of gaining insight into the pathogenesis of fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF), with hopes of discovery of potential new therapeutic targets. Dr. Fan will study fibroblast activation protein (FAP)-a type II integral cell surface serine protease with dipeptidyl peptidase, endopeptidase, and collagenase activity-as a critical factor in the development of pulmonary fibrosis. Ellen Pure, PhD, will serve as Dr. Fan's scientific mentor throughout her investigations. Dr. Pure is a world-renowned expert in the field of CD44 signaling and regulation with a special interest in inflammation, cancer biology, and fibrosis. Dr. Fan will also have additional guidance from a scientific advisory committee, which includes Dr. Michael Beers, an expert in interstitial lung disease and surfactant biology who will co-sponsor this grant, as well as Dr. Steven Albelda, Vice Chief and Director of Lung Research of the Pulmonary, Allergy, and Critical Care Division at the Hospital of University of Pennsylvania. Dr. Fan's project will determine the mechanism(s) by which FAP protects against the development of pulmonary fibrosis after lung injury. Preliminary data demonstrates decreased survival and increased pulmonary fibrosis in FAP-deficient mice vs. wildtype in two pulmonary fibrosis models-thoracic irradiation and intratracheal bleomycin-establishing a protective role for FAP in the pathogenesis of the disease. Specific Aims 1, 2, and 3 will determine the mechanism(s) by which this occurs. Specific Aim 1 will examine whether increased pulmonary fibrosis is seen in FAP-deficient mice compared to wildtype due to loss of FAP's known specific protease activities. Specific Aim 2 will examine for 1) alterations in fibroblast phenotype, 2) changes in active TGFb levels and signaling, and/or 3) alterations in ECM components occurring in the setting of FAP deficiency that might explain the pro-fibrotic phenotype. Specific Aim 3 will explore a possible immuno- modulatory role for FAP. Specific Aim 4, through the use of novel pharmacologic FAP inhibitors, will determine the effect of acute loss of FAP activity on the development of pulmonary fibrosis after lung injury, complementing our earlier genetic studies. While FAP has generated intense interest in the field of cancer biology as a potential target for antitumor drugs, it is a relatively under-studied protein in the field of fibrosis research. Our findings and experimental plan represent a novel direction in our understanding of the workings of this protein with potential implications for the treatment of interstitial lung diseases in the future. The sponsoring institutions-the Wistar Institute and the University of Pennsylvania-provide a wealth of opportunities for Dr. Fan's scientific development. She has already developed collaborations with investigators at the University of Pennsylvania and the Institute of Medicine and Engineering in Philadelphia. She has the full support of her scientific mentor, Ellen Puri, as well as her department in her pursuit of an academic career as a physician-scientist. PUBLIC HEALTH RELEVANCE: This application aims to gain insight into the pathogenesis of fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF), with hopes of discovery of potential new therapeutic targets, through the study of fibroblast activation protein (FAP), a type II integral cell surface serine protease with dipeptidyl peptidase, endopeptidase, and collagenase activities. Our preliminary data demonstrates decreased survival and increased pulmonary fibrosis in FAP-deficient mice vs. wildtype in two pulmonary fibrosis models, establishing a protective role for FAP in the pathogenesis of the disease. Dr. Fan's project will determine the mechanism(s) by which FAP protects against the development of pulmonary fibrosis after lung injury.